Acquired factor V deficiency in an elderly hemodialysis patient: a case report and literature review

Abstract

Background

Acquired factor V deficiency (AFVD) is a rare hemorrhagic disorder caused by autoantibodies against coagulation factor V. Clinical manifestations vary widely, ranging from asymptomatic cases to severe hemorrhage or even thrombosis, and diagnosis is often challenging due to its rarity and nonspecific presentation. Reported triggers include bovine thrombin, antibiotics, surgery, autoimmune diseases, infections, and malignancy, although up to 20% of cases are idiopathic. We report a case of AFVD in an elderly hemodialysis patient, in whom corticosteroid therapy was effective but ultimately complicated by fatal gastrointestinal bleeding.

Case presentation

An 87-year-old woman on hemodialysis for diabetic nephropathy was admitted with acute cholecystitis and treated with ceftriaxone. On day 16, she developed bleeding from a gastrostomy site with markedly prolonged prothrombin time (69.3 s) and activated partial thromboplastin time (260.4 s). Cross-mixing studies showed inhibitor patterns, and factor V activity was reduced to 1.3%, with an inhibitor titer of 33.3 Bethesda units/mL, confirming AFVD. Despite no bleeding from vascular access sites, she developed progressive anemia and gingival bleeding. Intravenous prednisolone (40 mg/day) was initiated, resulting in normalization of coagulation parameters and recovery of factor V activity to 111.7% within 30 days. However, on day 57, she developed massive melena. Endoscopy revealed hemorrhagic duodenal ulcers with exposed vessels, requiring endoscopic hemostasis. Recurrent gastrointestinal bleeding occurred on day 61, and she died of hemorrhagic shock.

Conclusions

This case illustrates the diagnostic process and therapeutic challenges of AFVD in a hemodialysis patient. Corticosteroid therapy was effective in eradicating the inhibitor and restoring factor V activity, but fatal gastrointestinal bleeding occurred as a severe treatment-related complication. Clinicians should be aware of AFVD as a rare but important cause of acquired coagulopathy, and careful monitoring for corticosteroid-associated adverse effects is crucial, especially in elderly and critically ill individuals.

Background

Acquired factor V deficiency (AFVD) is a rare acquired coagulation disorder caused by the development of autoantibodies against factor V. Because both the extrinsic and intrinsic coagulation pathways are affected, AFVD typically presents with simultaneous prolongation of prothrombin time (PT) and activated partial thromboplastin time (APTT), a laboratory pattern that necessitates careful differential diagnosis.

AFVD has been associated with various clinical conditions, including infection, antibiotic exposure, surgery, malignancy, autoimmune disease, and blood transfusion, although a substantial proportion of cases remain idiopathic [1]. In clinical practice, AFVD is often difficult to recognize promptly because its laboratory abnormalities can mimic more common conditions such as vitamin K deficiency or liver dysfunction.

Only a small number of cases of AFVD have been reported in patients undergoing maintenance hemodialysis, and the clinical features and optimal management strategies in this population remain poorly defined. We herein report a case of AFVD in an elderly patient receiving maintenance hemodialysis, highlighting the diagnostic process and the therapeutic challenges associated with immunosuppressive treatment in this vulnerable patient.

Case presentation

In September 2020, an 87-year-old woman was admitted to our hospital for evaluation of high fever and right upper quadrant pain. She had been diagnosed with Lewy body dementia in 2016 and was bedridden. Due to dementia-associated dysphagia, she became unable to take food orally and a gastrostomy tube was placed. In 2017, she started hemodialysis for end stage kidney disease (ESKD) caused by diabetic nephropathy.

At the time of presentation, the patient was 151 cm tall and weighed 37.0 kg. Her blood pressure was 136/56 mmHg, and temperature was 37.8 °C. Her palpebral conjunctiva was pale, and severe tenderness with rebound was observed from the right upper quadrant to epigastric region. She was diagnosed with acute cholecystitis. Given her advanced age and poor performance status, invasive interventions such as surgery were deemed inappropriate, and antibiotic therapy was initiated with ceftriaxone (CTRX). Cholecystitis improved with treatment, accompanied by resolution of fever and decreased inflammatory markers. However, on day 16 of hospitalization, laboratory testing revealed markedly prolonged coagulation times, with a PT of 69.3 s and an APTT of 260.4 s (Table 1). In addition, bleeding was observed from the gastrostomy site.

Table 1.

Coagulation test (On day 16 of hospitalization)

APTT		Reference range
	260.4	23.5–35.0	s
PT, s	69.3	10.0–15.0	s
PT, %	8	70.0–130.0	%
PT-INR	6.94	0.85–1.30
Fibrinogen	631	180–350	mg/dL
FDP	3.2	0.0–4.0	µg/mL
D-dimer	1.1	0.0–1.0	µg/mL

The laboratory examination results are presented in Table 2. Hemoglobin was reduced, with a normal platelet count. A blood coagulation test revealed marked abnormalities. Diluted Russell’s viper venom time for the detection of lupus anticoagulants was markedly prolonged (over 150 s, normal 30 to 40 s) and thus the results were inconclusive.

Table 2.

Laboratory data

White blood cell		Reference range
	14,700	3,500–9,000	/µL
(Neutrophil)	88.7	40–70	%
(Lymphocyte)	3.5	20–40	%
(Monocyte)	5.4	2–8	%
(Eosinophil)	1.7	1–6	%
Red blood cell	268	380–500	×10⁴ /µL
Hemoglobin	8.6	11.5–15.0	g/dL
Platelets	22	15–35	×10⁴ /µL
Albumin	2.4	3.8–5.3	g/dL
Urea nitrogen	37.1	8–20	mg/dL
Creatinine	3.75	0.46–0.82	mg/dL
Aspartate aminotransferase	10	13–33	IU/L
Alanine aminotransferase	5	8–42	IU/L
Alkaline phosphatase	245	115–359	IU/L
Gamma-glutamyl transferase	8	7–32	IU/L
C-Reactive Protein	7.52	<0.3	mg/dL

Given the possibility of vitamin K deficiency associated with antibiotic use, intravenous menatetrenone was administered; however, the coagulation abnormality did not improve. In addition, fresh frozen plasma (FFP) was administered to replace coagulation factor deficiencies, but no improvement in the coagulation data was observed. A cross-mixing test of PT and APTT using a stocked plasma sample was performed to search for the cause of the abnormal coagulation. The cross-mixing test consists of two components: an immediate-type reaction, in which the coagulation time is measured immediately after mixing normal and patient plasma; and a delayed-type reaction, in which the coagulation time is measured after incubation at 37 °C for 2 h [2]. In the present case, both the immediate and delayed reactions showed a convex upward curve, with a more pronounced change observed in the delayed reaction (Fig. 1). These findings were suggestive of the presence of coagulation factor inhibitors. Prolongation of both PT and APTT suggested an abnormality in the common pathway of the coagulation cascade. Factor V activity was subsequently measured and found to be 1.3%, and the factor V inhibitor titer was 33.3 Bethesda units (B.U.)/mL (Table 3). Based on these findings, a diagnosis of AFVD was made.

Fig. 1.

Cross mixing tests. The immediate reaction (no incubation) and the reaction after 2 h of incubation (2 h incubation) showed upward convex graph patterns, suggesting the presence of inhibitors

Table 3.

Coagulation factor activity test

Coagulation factor assay		Reference range
Ⅴ	1.7	70–140%
Ⅷ	120	70–130%
Ⅹ	98.5	70–120%
Factor Ⅴ inhibitor	33.3	B.U./mL
von Willbrand factor	> 200	50–155%

No bleeding was observed at the arteriovenous fistula puncture sites during hemodialysis, and no prolongation of bleeding time. However, she subsequently developed not only bleeding from the gastrostomy site but also gingival bleeding. Due to the progression of anemia and the presence of significant hemorrhagic symptoms, corticosteroid therapy was initiated. Intravenous administration of prednisolone sodium succinate at a dose of 40 mg/day (1 mg/kg) was initiated. Proton pump inhibitor (PPI) therapy was initiated concomitantly with prednisolone as prophylaxis against gastrointestinal complications (Table 4).

Table 4.

Medications at admission and during the clinical course

Medication	Indication	Dose	Route	Timing	Duration / Status
CTRX	Acute cholecystitis	2 g/day	Intravenous	Hospital day 1	Discontinued after 18 days
Amlodipine	Hypertension	5 mg/day	Oral	At admission	Continued
Prednisolone sodium succinate	AFVD	1 mg/kg/day	Intravenous	Hospital day 23	Continued with gradual tapering
Omeprazole	Gastrointestinal prophylaxis	40 mg/day	Intravenous	At prednisolone initiation	Continued

Both PT and APTT gradually normalized, and by day 45 of hospitalization, the factor V inhibitor titer had decreased to 0.37 B.U./mL, with a concomitant improvement in factor V activity to 111.7% (Fig. 2). Since the patient exhibited markedly prolonged PT and APTT from admission, along with bleeding, nafamostat mesylate used was consistently used as the anticoagulant during dialysis throughout the hospitalization. No bleeding or hemostatic abnormalities related to vascular access were observed, and no dialysis-associated hemorrhagic complications occurred. However, on day 57, she developed massive melena. Upper gastrointestinal endoscopy revealed hemorrhagic duodenal ulcers, and endoscopic hemostasis was performed by coagulation visible vessels (Fig. 3a-b). The previously administered PPI was continued. Although initial control of bleeding was achieved, on day 61, she developed recurrent massive gastrointestinal bleeding and died of hemorrhagic shock.

Fig. 2.

Clinical course. CTRX: ceftriaxone, FFP: fresh frozen plasma, APTT: activated partial thromboplastin time, PT: prothrombin time, FV: factor Ⅴ

Fig. 3.

Findings of upper gastrointestinal endoscopy. a: Multiple ulcers were observed extending from the duodenal bulb to the superior duodenal angle. Blackish-brown mucus was adherent to the ulcer bases. b: An exposed vessel was identified at the base of an ulcer located in the superior duodenal angle (yellow circle)

Discussion and conclusions

AFVD in the setting of hemodialysis

AFVD is an extremely rare bleeding disorder caused by the development of autoantibodies against coagulation factor V. Although AFVD has been reported in patients receiving maintenance hemodialysis, the number of published cases remains limited, and the reported clinical features are highly heterogeneous. Proposed precipitating factors include infection, antibiotic exposure, surgery, transfusion, and initiation of hemodialysis [3]. These observations suggest that hemodialysis itself is unlikely to be a direct causal factor; rather, it represents a clinical background characterized by chronic inflammation, immune dysregulation, and repeated immunologic stimulation that may predispose patients to autoantibody formation.

Review of previously reported cases

We reviewed published case reports and series describing AFVD occurring during maintenance hemodialysis or around the initiation of hemodialysis. Eligible cases were defined by reduced factor V activity and/or detection of a factor V inhibitor and are summarized in Table 5.

Table 5.

Summary of reported cases of acquired factor V deficiency in maintenance Hemodialysis patients

Reference	Patient background	Trigger / precipitating factor	Inhibitor (titer)	Main presentation	Treatment	Outcome	Treatment response
Ishizu et al. [4]	Maintenance HD, Japan	Not specified	AFVI (high, exact titer NR)	Severe bleeding tendency	Supportive care (details not reported)	Improved	Not reported
Niwa et al. [5]	Maintenance HD	Infection/ antibiotics	FV + FVIII inhibitors (titer NR)	Renal hemorrhage, required TAE	TAE, PSL	Remission	Inhibitor disappeared
Ogawa et al. [6]	Maintenance HD	Not specified	AFVI (very high, FV < 1%)	Arterial thrombosis despite bleeding risk	Supportive + immunosuppression	Improved	Details NR
Zhao et al. [1]	Maintenance HD	Not specified (no inhibitor)	Negative	Massive pleural/pericardial bleeding, lymphatic leakage suspected	FFP, supportive	Improved	No inhibitor detected
Kitazawa et al. [7]	ESKD, warfarin use -> chronic HD	Possibly antibiotics/ ESKD-related	AFVI (titer NR)	Bleeding tendency during ESKD, later on HD	PSL	Remission	Inhibitor status NR
Matsumoto et al. [8]	HD initiation	Infection/ antibiotics	AFVI (titer NR)	Severe bleeding, difficult to control	Multimodal (steroids, transfusion, others)	Controlled	Clinical hemostasis achieved
Tasaki et al. [9]	HD initiation after SARS-CoV-2 vaccination	Vaccination	AFVI (present, low activity)	No major bleeding	Supportive (no immunosuppression)	Stable on HD	No immunosuppression; stable course
Katsuren et al. [10]	ESKD, AV fistula surgery	Drug eruption, eosinophilia	AFVI (145 BU/mL)	Surgical site bleeding	PSL 1 mg/kg	Remission	Inhibitor disappeared

Early reports from Japan described maintenance hemodialysis patients who developed AFVD with severe hemorrhagic manifestations [4]. Subsequent reports expanded the clinical spectrum to include cases with concurrent factor V and factor VIII inhibitors complicated by renal hemorrhage [5], high-titer factor V inhibitors associated with arterial thrombosis [6], and AFVD with massive serous cavity bleeding without detectable inhibitors, suggesting alternative pathogenic mechanisms such as lymphatic leakage [1]. AFVD has also been described at the time of hemodialysis initiation. Reported cases include AFVD developing before chronic dialysis [7], cases occurring shortly after dialysis induction often in association with infection and antibiotic exposure [8], and a case following SARS-CoV-2 vaccination in which factor V inhibitors were detected without severe bleeding, allowing continuation of dialysis without immunosuppressive therapy [9]. Together, these reports highlight the diversity of clinical presentations and the importance of recognizing potential triggering events in patients with ESKD.

Clinical characteristics of the present case

The present case represents a severe manifestation of AFVD in an extremely elderly, bedridden patient undergoing maintenance hemodialysis. In contrast to many previously reported cases in which bleeding occurred at vascular access sites or in relation to dialysis procedures, our patient developed overt bleeding from a gastrostomy site without any dialysis-related complications. This finding underscores that bleeding manifestations in hemodialysis patients are not invariably procedure-related. Therefore, sudden and unexplained prolongation of both PT and APTT, particularly when accompanied by non–access-related bleeding, should prompt early consideration of AFVD, even when more common etiologies such as vitamin K deficiency or hepatic dysfunction appear plausible.

Possible triggers and the role of antibiotic exposure

Although the patient had multiple known risk factors for CTRX-associated pseudolithiasis, including hypoalbuminemia, diabetes mellitus, prolonged immobility, and advanced kidney failure requiring hemodialysis, CTRX was selected because of its broad antimicrobial coverage for acute cholecystitis, favorable biliary penetration, and suitability for use in patients undergoing hemodialysis. Baseline imaging revealed no gallstones or biliary sludge, and CTRX was administered for a limited duration with close monitoring, without subsequent pseudolithiasis. Importantly, the close temporal relationship between acute cholecystitis treated with CTRX and the abrupt onset of marked PT and APTT prolongation supports the hypothesis that infection- and/or antibiotic-related immune activation contributed to the development of the factor V inhibitor.

Pathophysiology and treatment considerations

Factor V is a critical cofactor in the coagulation cascade, participating in the formation of the prothrombinase complex that converts prothrombin to thrombin. Inhibitors against factor V disrupt this process by interfering with factor V binding to phospholipid surfaces. Notably, the severity of bleeding does not necessarily correlate with inhibitor titers. Some patients remain asymptomatic despite markedly reduced or even undetectable plasma factor V levels, whereas others may experience bleeding complications even with only mild factor V inhibition. One proposed explanation is that factor V stored in platelet α-granules may be relatively protected from circulating inhibitors and released locally at sites of vascular injury, thereby contributing to hemostasis [2].

Management of AFVD focuses on control of active bleeding and eradication of the inhibitor. In previously reported cases of AFVD, systemic corticosteroids have been used as first-line therapy, with prednisolone doses ranging from 0.5 to 1.0 mg/kg/day. Notably, higher doses have frequently been selected in patients with high inhibitor titers in order to achieve rapid suppression of autoantibody production and early improvement of coagulation abnormalities. There is currently no evidence that cyclophosphamide is superior to corticosteroids as initial therapy, nor that it confers a lower risk of gastrointestinal bleeding, particularly in frail elderly patients or those undergoing hemodialysis. Plasma exchange has been used in life-threatening bleeding but provides only transient benefit because it does not suppress autoantibody production [11].

In the present case, the markedly elevated inhibitor titer at diagnosis prompted initiation of high-dose prednisolone. This strategy resulted in a rapid decline in inhibitor levels, indicating effective immunological suppression. However, despite prophylactic PPI therapy, the patient subsequently developed massive duodenal ulcer bleeding at a time when inhibitor titers had already decreased. This clinical course suggests that the fatal hemorrhagic event was more likely related to corticosteroid-associated gastrointestinal toxicity rather than ongoing AFVD activity.

Conclusions

We report a rare and severe case of AFVD in an elderly patient undergoing maintenance hemodialysis. Corticosteroid therapy was effective in reducing inhibitor titers; however, the patient ultimately died from gastrointestinal bleeding. This case highlights the need for early recognition of AFVD in hemodialysis patients with unexplained prolongation of PT and APTT and non–procedure-related bleeding. At the same time, it underscores the importance of carefully balancing the benefits and risks of immunosuppressive therapy in frail and critically ill patients.

Abbreviations

AFVD

Acquired factor V deficiency

ESKD

End stage kidney disease

CTRX

Ceftriaxone

PT

Prothrombin time

APTT

Activated partial thromboplastin time

PT-INR

Prothrombin time-international normalized ratio

FDP

Fibrinogen degradation product

FFP

Fresh frozen plasma

PPI

Proton pump inhibitor

AFVI

Acquired factor V inhibitor

AV

Arteriovenous

FV

Factor V

FVIII

Factor VIII

HD

Hemodialysis

PSL

Prednisolone

TAE

Transcatheter arterial embolization

NR

Not reported

Author contributions

All authors read and approved the final manuscript.

Funding

The authors received no specific funding for this work.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Informed consent for publication of the clinical details and images was obtained from the patient.

Competing interests

The authors declare no competing interests.